Elucidating cutaneous mechanosensory circuits, from development to disease

摘要 触觉使我们能够感知并对物理世界做出反应--我们识别物体 握在我们的手中，区分不同的质地和形状，以及感觉-运动 反馈电路协调我们的身体动作。触觉也是各种形式的 社会交换，因此是人类经验的一个重要组成部分。第一步 导致触觉的是一组名为LOW的皮肤感觉神经元的激活 机械阈值受体(LTMR)。有几种LTMR类型，每种类型都有一个唯一的 敏感度，形态，生理特性，大概还有功能。了解 每种LTMR类型的独特功能，以及LTMR活动的集合如何集成和 在中枢神经系统中加工形成触觉是该领域的突出问题。因此， 我的实验室以及这份R35提案的总体目标是：1)阐明敏感性， 哺乳动物主要皮肤的兴奋机制和独特功能 LTMR；2)定义脊髓和脑干中LTMR电路组织的逻辑，以及 通向大脑的上升通道的性质，是区别对待和情感触摸的基础 感知；3)确定外周躯体感觉系统是如何在 开发；以及4)确定触摸电路及其功能障碍是否以及如何 自闭症谱系障碍和神经病理性疼痛中的触觉缺陷是发育的基础。 我们正在使用一系列强大的老鼠分子遗传工具，结合在一起，实现这些目标 通过复杂的电生理、解剖学、行为和发育分析。 成功完成这一R35‘S目标将由此揭示躯体感觉神经的机制 系统的开发和功能，以及脊髓触摸信息处理的底层 知觉，在正常和疾病条件下。

Abstract The sense of touch allows us to perceive and respond to the physical world –we recognize objects held in our hands, discriminate between different textures and shapes, and sensory-motor feedback circuits coordinate our body movements. The sense of touch also underlies forms of social exchange and is thus an essential component of the human experience. The first step leading to touch perception is activation of a group of cutaneous sensory neurons called low- threshold mechanoreceptors (LTMRs). There are several LTMR types, and each has a unique sensitivity, morphology, physiological property and, presumably, function. Understanding the unique functions of each LTMR type, and how ensembles of LTMR activities are integrated and processed in the CNS to form touch percepts are outstanding questions in the field. Therefore, the overall goals of my laboratory, and thus this R35 proposal, are: 1) to elucidate the sensitivities, mechanisms of excitation, and unique functions of the major classes of mammalian cutaneous LTMRs; 2) to define the logic of LTMR circuit organization in the spinal cord and brainstem, and the nature of ascending pathways to the brain that underlie discriminative and affective touch perception; 3) to establish how the peripheral somatosensory system assembles during development; and 4) to determine whether and how dysfunction of touch circuits and their development underlies tactile deficits in autism spectrum disorders and during neuropathic pain. We are achieving these goals using an array of powerful mouse molecular genetic tools, combined with sophisticated electrophysiological, anatomical, behavioral and developmental assays. Successful completion of this R35's goals will thus reveal mechanisms of somatosensory nervous system development and function, and spinal cord touch information processing underlying perception, under normal and disease conditions.